TY - JOUR
T1 - Stereocontrolled synthesis and pharmacological evaluation of azetidine-2,3-dicarboxylic acids at NMDA receptors
AU - Sivaprakasam, Mangaleswaran
AU - Hansen, Kasper B.
AU - David, Olivier
AU - Nielsen, Birgitte
AU - Traynelis, Stephen F.
AU - Clausen, Rasmus P.
AU - Couty, François
AU - Bunch, Lennart
PY - 2009/1/12
Y1 - 2009/1/12
N2 - The four stereoisomers of azetidine-2,3-dicaroxylic acid (L-trans-ADC, L-cis-ADC, D-trans-ADC, and D-cis-ADC) were synthesized in a stereocontrolled fashion following two distinct strategies: one providing the two cis-ADC enantiomers and one giving access to the two trans-ADC enantiomers. The four azetidinic amino acids were characterized in a radioligand binding assay ([ 3H]CGP39653) at native NMDA receptors: L-trans-ADC showed the highest affinity (Ki = 70 μM) followed by the D-cis-ADC stereoisomer (21 μM). In contrast, the two analogues L-cis-ADC and d-trans-ADC were low-affinity ligands (> 700 and 90μM, respectively). Electrophysiological characterization of the ADC com-pounds at the four NMDA receptor subtypes NR7/NR2A, NR1/NR2B, NR1/NR2C, and NR7/NR2D expressed in Xenopus oocytes showed that L-trans-ADC displayed the highest agonist potency at NR1/NR2D (EC 50 = 50μM), which was 9.4-, 3.4-, and 7.9-fold higher than the respective potencies at NR7/NR2A-C. D-cis-ADC was shown to be a partial agonist at NR1/NR2C and NR1/NR2D with medium-range micromolar potencies (EC50 = 720 and 230 μm, respectively). A subsequent in silico ligand-protein docking study suggested an unusual binding mode for these amino acids in the agonist binding site.
AB - The four stereoisomers of azetidine-2,3-dicaroxylic acid (L-trans-ADC, L-cis-ADC, D-trans-ADC, and D-cis-ADC) were synthesized in a stereocontrolled fashion following two distinct strategies: one providing the two cis-ADC enantiomers and one giving access to the two trans-ADC enantiomers. The four azetidinic amino acids were characterized in a radioligand binding assay ([ 3H]CGP39653) at native NMDA receptors: L-trans-ADC showed the highest affinity (Ki = 70 μM) followed by the D-cis-ADC stereoisomer (21 μM). In contrast, the two analogues L-cis-ADC and d-trans-ADC were low-affinity ligands (> 700 and 90μM, respectively). Electrophysiological characterization of the ADC com-pounds at the four NMDA receptor subtypes NR7/NR2A, NR1/NR2B, NR1/NR2C, and NR7/NR2D expressed in Xenopus oocytes showed that L-trans-ADC displayed the highest agonist potency at NR1/NR2D (EC 50 = 50μM), which was 9.4-, 3.4-, and 7.9-fold higher than the respective potencies at NR7/NR2A-C. D-cis-ADC was shown to be a partial agonist at NR1/NR2C and NR1/NR2D with medium-range micromolar potencies (EC50 = 720 and 230 μm, respectively). A subsequent in silico ligand-protein docking study suggested an unusual binding mode for these amino acids in the agonist binding site.
KW - Conformational restriction
KW - Enantioselectivity
KW - Glutamate
KW - NMDA
KW - Receptors
UR - http://www.scopus.com/inward/record.url?scp=58549090123&partnerID=8YFLogxK
U2 - 10.1002/cmdc.200800226
DO - 10.1002/cmdc.200800226
M3 - Article
C2 - 19009584
AN - SCOPUS:58549090123
SN - 1860-7179
VL - 4
SP - 110
EP - 117
JO - ChemMedChem
JF - ChemMedChem
IS - 1
ER -